PROJECT SUMMARY Insulin-like growth factor (IGF) signaling is an evolutionarily conserved system regulating aging and age- related diseases. Global reduction of IGF signaling by various genetic means results in lifespan extension. Tissue-specific reduction in IGF signaling has not been shown to recapitulate this longevity phenotype, except in the brain. This is of interest, because the brain could link neuroendocrine function to systemic aging. Partial inactivation of IGF-I receptor (IGF-IR) or a down-stream signal transduction molecule for IGF-IR in brain increased lifespan in mice. Partial inhibition is key to beneficial effects, since complete inhibition resulted in profound negative effects in these mice. Regulation of IGF-IR signaling can also be achieved though the action of pregnancy-associated plasma protein-A (PAPP-A). PAPP-A is a novel zinc metalloprotease that can increase local IGF-I bioavailability through cleavage of inhibitory IGF binding proteins. Conversely, inhibition of PAPP-A expression or its proteolytic activity represents an innovative approach to decreasing IGF availability with moderate restraint of IGF-IR signaling. We have shown that global PAPP-A knock-out (KO) mice live 30-40% longer than wild-type littermates. Conditional knock-down of PAPP-A in adult mice has also been shown to extend lifespan. However, no tissue-specific PAPP-A KO mouse model has been developed as yet. We propose to generate brain-specific PAPP-A KO mice, based on previously published studies by others showing reduction in IGF-IR signaling in brain increased lifespan in mice, our studies demonstrating that PAPP-A KO mice are long-lived, and the knowledge that PAPP-A is expressed in the mouse brain and that its expression increases with age. The Specific Aims are to (1) Generate brain-specific PAPP-A KO by crossing our floxed PAPP-A mice with Nestin-Cre mice; (2) Characterize the consequences of PAPP-A deletion in the brain on morphogenic and metabolic parameters of brain-specific PAPP-A KO mice with diet and age. The proposed studies would be the first to generate and characterize a novel tissue-specific PAPP-A KO mouse model to study the role of brain PAPP-A in promoting healthy longevity.